We have now cloned and sequenced the murine apoB48 receptor cDNA and gene, the equivalent of the human monocyte apoB48 lipoprotein receptor, a new and unique protein (no significant homologies in GenBank) we cloned previously with a predicted MW of 115 KD and an mRNA of3.8 kb. The human cDNA (3744 bp) has a Kozak consensus start site, predicts a leader sequence and a transmembrane domain, has a 3 untranslated sequence with a polyadenylation signal and a poly A tail. The cell and tissue distribution in humans appears restricted to reticuloendothelial cells: monocytes, macrophages, placenta, bone marrow, immune tissue (tonsil, lymph nodes, the appendix). Immunohistochemical studies demonstrate that this receptor co-localized with macrophage-specific markers to the macrophage foam cells of human aortic fatty streak and atherosclerotic carotid and coronary lesions and the macrophages of immune tissues. We hypothesize that this receptor may play a role in nutrition of circulating monocytes in normal states and may contribute to foam cell formation and atherogenesis in disease states. Murine macrophages (M) constitutively express a receptor with identical ligand specificities and binding kinetics as the human (hu) apoB48R, which is unlike any known protein, is restricted to reticuloendothelial cells and may deliver essential lipid nutrients to peripheral Ms. Of note, apoEnullVLDL fromapoE-deficient (apoE-/-) mice bind to the hu apoB48 R on ligand blots and are rapidly and specifically internalized by THP-1 Ms via this receptor and CHOs transfected with the hu apoB48R is likely involved in the spontaneous, extensive foam cell formation and atherosclerosis of apoE(-/-) mice, in which apoB48-containing particles predominate in plasma. As a first step toward creating apoB48 R knockout mice, we have cloned the mu apoB48R cDNA (strain 129) and gene. We sequenced the mu apoB48R cDNA (3615 bp). The deduced protein sequence [103 kDa, 942 amino acids (aa)] is homologous to the hu apoB48R(~115 kDa, 1088 aa) but to no other proteins in GenBank. The first 54 aa and the last 36 aa are highly homologous (>80%), with an overall ~45% protein sequence homology. The hu and mu genes are similarly organized with 4 exons interspersed with 3 small introns. Both proteins have potential coiled-coil regions in analogour positions that could promote the homodimerization that appears to account for the differences in deduced and apparent Mrs (mu, ~190 kDa; hu ~200 kDa). Future studies with apoB48R (-/-) abd transgenic mice are needed to determine the role in vivo of this unique receptor in lipoprotein metabolism, peripheral macrophage lipid metabolism, foam cell formation and atherosclerosis.